BAFF is a TNF-like cytokine that supports survival and selection of B cells and together with its three receptors BAFF-R, TACI and BCMA, augments both innate and adaptive immune responses. The homologous molecule APRIL binds to TACI and BCMA and is an important mediator of plasma cell survival. The successful use of BAFF/APRIL inhibitors in murine models of autoimmunity has led to the rapid development of this class of drugs for clinical testing in humans. The first of these drugs, belimumab, a monoclonal antibody specific for soluble BAFF, has demonstrated efficacy in phase 3 studies of moderately active SLE and is now approved for SLE treatment. Other drugs of this class including atacicept, an inhibitor of both BAFF and APRIL, and blisibimod, a BAFF antagonist, have demonstrated efficacy in phase 2 and are moving forward into phase 3 studies. Despite these exciting advances, the modest effect of belimumab over current standard of care therapies, with clinical responses in only 50% of treated patients, mandate that we better understand the biology of BAFF and APRIL in SLE, so that we can use this intervention to maximal therapeutic effect. The first two aims of this proposal will focus on the contribution of BAFF to the major stages of B cell survival, selection and activation in Ig transgenic murine SLE models and in human SLE patients and will uncover the effects of BAFF inhibition on B cells at each B cell developmental stage. These studies should determine the effects of BAFF inhibition on the survival and selection of autoreactive B cells at multiple checkpoints and will determine for the first time whether belimumab actually alters B cell selection in all or some SLE patients and over what time frame. In the third aim of this proposal we will begin to investigate the role o BAFF/BAFF-R interactions in immune cells other than B cells, particularly peripheral blood monocytes. These studies will begin to give insights into other potential mechanisms for the therapeutic efficacy of BAFF inhibition apart from regulating B cell selection.